(a) Field of the Invention
This invention relates to novel substituted (azacycloalk-2-yl)iminophenols of Formula I that are useful in the treatment of diarrhea.
Diarrhea is a condition characterized by an abnormally frequent discharge of liquid or semi-liquid from the bowel. The normal intestinal discharge occurs at variable intervals but usually not more than twice in twenty-four hours and typically has a semi-solid consistency. When a more liquid stool must be discharged more than three times a day, diarrhea exists. Diarrhea may have any of several causes. For example, eating indigestible or irritating foods or foods to which an individual is allergic may cause diarrhea. Too much roughage, such as found in bran, cabbage, or other fibrous foods often consumed to relieve constipation, may also induce diarrhea. Infection or nervousness, which can cause discharge before the intestinal contents can assume a normal form, are causes of diarrhea. Moreover, many drugs, particularly antibiotics, are known to cause diarrhea as a side effect.
Mild diarrhea has been treated with binding agents such as aluminum hydroxide gel, kaolin, pectin, and bismuth. More serious diarrhea has been treated with opiates, which act through a spasmogenic effect that inhibits propulsive activity in the intestine. Diphenoxylate (a synthetic opiate derivative), tincture of opium, and camphorated tincture of opium (paregoric) have all been used effectively for serious diarrhea. The compounds, however, treat symptoms rather than causes and have all the problems associated with opiates, such as addictive liability, mental confusion or discomfort, respiratory depression, nausea, and the like. Thus, care must be taken to avoid complications and even death.
(b) Prior Art
Certain phenyl-substituted cyclic amidines are known, but differ significantly from compounds of the present invention. U.S. Pat. No. 3,769,274 and U.S. Ser. No. 06/433,922, now U.S. Pat. No. 4,533,739, issued Aug. 6, 1985, the latter having the same assignee as this application, include compounds having amino or substituted-amino groups but do not disclose hydroxy or acyloxy groups on the phenyl nucleus. Only '922 discloses and claims antidiarrheal activity for these previously disclosed compounds.
U.S. Pat. No. 3,563,994 discloses compounds in which the phenyl substituents include, inter alia, alkoxy, alkanoyl (i.e., ketone compounds), or alkoxycarbonyl (i.e., benzoate ester compounds). In addition, the '994 patent discloses only antihypertensive activity, CNS damping effects, and inhibition of gastric acid (as opposed to intestinal fluid) secretion. The '994 patent, however, does not claim nor disclose compounds of this invention, in which phenyl substituents include hydroxy or acyloxy (i.e., phenolic ester compounds). Moreover, selected compounds encompassed within the '994 patent--two methoxy-substituted and one methoxycarbonyl-substituted analog--were found to be inactive or only weakly active in antisecretory antidiarrheal assays in which the compounds of this invention were, in sharp contrast, quite active.